Analyzer with sample quality measurement, and method

ABSTRACT

A system for detecting and analyzing patient sample quality and/or analytes, while the sample is in the metering tip used to aspirate the sample liquid from an original patient sample container, and also to dispense the liquid onto a slide test element. Spectrophotometric analysis may be done on the sample liquid while it is still in the tip which has been converted into a cuvette. One technique for such analysis is by scanning the cuvette for transmittance in a light-tight enclosure. Near-infrared and adjacent visible radiation may be used, and the absorption spectra of the liquid detected and analyzed. A possible aspect of the present invention relates to enhancing throughput of an analyzer by conducting a sample quality measurement in a process that is parallel to the main analyzer timing cycle. Another possible aspect of the present invention relates to improving performance of the analyzer by sealing the end of the metering tip to spontaneously form a cuvette for holding the sample during the sample quality measurement. Some advantages of the present system and method include improved throughput, the capability to use smaller sample liquid volumes, eliminating any need for a separate supply of cuvettes independent of the metering tips, and providing for detection through a cone of the metering tip rather than through any label, compared to doing the scanning of the sample liquid in a primary patient collection container.

CROSS RELATED TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.09/658,356, filed Sep. 11, 2000 now U.S. Pat. No. 6,797,518 .

BACKGROUND AND SUMMARY OF THE INVENTION

1. Technical Background

The present invention relates generally to systems and methods foranalyzing patient samples.

2. Discussion

Spectrophotometric analysis is often applied to liquid samples todetermine their contents. In general, the term “spectrophotometric”refers to capturing spectral response over a range of wavelengths andcorrelating a response for each of the wavelengths. A device thatperforms this analysis is referred to as a “spectrophotorheter.” Suchspectrophotometric analysis has been performed with near-infrared andadjacent visible radiation, which is capable of ascertaining hemoglobin,glucose, albumin, lipoproteins, and many other sera components.

One challenge in performing spectrophotometric analysis has been thatthe samples are initially obtained in a variety of primary patientcollection containers. These containers are usually tubes of varyingdiameters and lengths. In the case of a patient blood sample, the liquidis often centrifuged to separate the liquid serum or plasma from thecellular phases. Such tubes may have a patient identification label,varying and unpredictable amounts of the sera to be analyzed in thetotal sample, and contain a relatively large amount of sample liquid.

Prior spectrophotometric analysis systems are adequate to meet theirdesign criteria, and they generally aliquot a portion of the sample intoa secondary container or tube of a consistent size. This technique mayadd complexity and increase the time required for processing in a singlesample. This measure may introduce additional equipment expenses andprocessing delays, and may involve spectrophotometric scanning throughthe patient label.

Examples of successful analyzers having a spectrophotometric measurementthrough the metering tip are shown in (i) U.S. Pat. No. 5,846,492,entitled “Sample Quality Measurement And/Or Analyte Measurement InDispensing Tip Of An Analyzer,” issued to Jacobs et al. on Dec. 8, 1998;and also (ii) U.S. Pat. No. 6,013,528, entitled “Analyzer ThroughputFeaturing Through-The-Tip Analysis,” issued to Jacobs et al. on Jan. 11,2000, which are both incorporated by reference.

Many clinical analyzers provide a generally serial or linear path ofdependent events for processing each sample. This serial procedure isgenerally required to be performed in a specific order, and each stepmust be finished before the next can begin. For example, an analyzerprocess might include the steps of sample handling, aspirating a portionof the sample into a metering tip, dispensing a portion of the sampleonto a test element or slide, and then disposing of the tip. The timerequired to completely process a single sample may be referred to as theprocessing time, and each step of the total time can be referred to as atiming cycle or the “heartbeat.”

Such an analyzer might include various components, including a samplehandling bin or repository for holding primary collection containers, ametering probe or proboscis which can move around the stations of theanalyzer, one or more preferably disposable tips attached to theproboscis, and a metering pump connected to the proboscis for creatingpartial vacuum or partial pressure to selectively suck up into the tipor dispense a specific amount of sample liquid. In addition, analyzersoften include the components required for a thin film or wet chemistrysystem, such as a test element supply, an incubator, reagent and assaysupply, etc.

It is desirable in general to minimize the amount of the sample requiredfor use in an analyzer, because any portion of the sample that is usedfor a particular operation cannot be later used for another process oroperation. When the analyzer is in use, the component that actuallytouches the liquid of the sample is the tip.

Many of the metering tips used in analyzers are disposable, though thetip may also be permanent. Disposable tips generally have a relativelynarrow cylindrical end, connected to a small cone, which is in turnconnected to a larger generally cylindrical body. For optimum accuracyof the reading, and to minimize the amount of sample necessary, it isdesirable to do the spectrophotometric measurement through theintermediate cone of the metering tip.

As an example, the present invention will be described in relation toclinical analyzers and sample quality measurement. However, it should beunderstood that the present invention relates to any apparatus or methodhaving the features of the present invention, and is not limited to aparticular type of design.

One method of incorporating a sample quality capability into an analyzermight be to insert a sample quality measurement step in between the stepof aspirating the sample into the tip, and the step of dispensing thesample onto the test element. However, the sample quality measurementmight take as long as the amount of time to meter the sample onto thetest element. This particular method would therefore undesirablyincrease the length of the timing cycle of the analyzer. In addition,this particular method would undesirably require initially aspirating alarger portion of the sample, to raise the liquid level into theintermediate cone of the metering tip. Moreover, this technique mayrequire substantial enabling software to move the metering tip to a newlocation for the sample integrity reading.

Accordingly, the present invention preferably provides systems andmethods for analyzing and/or detecting the sample and/or analytes, whilethe sample is in the metering tip used to aspirate the sample liquid andalso dispense it onto a slide test element. In other words, thespectrophotometric analysis may be done on the sample liquid while it isstill in the tip which may be converted into cuvette, without requiringan additional container or cuvette, and may include a measurement ofsample quality.

A possible aspect of the present invention relates to enhancingthroughput of an analyzer by conducting a sample quality measurement ina process that is parallel to the main analyzer timing cycle. The samplequality measurement may thus be arranged after a portion of the samplehas already been dispensed onto the test element, and after the meteringtip has been removed from a proboscis. This novel method would eliminatea need for the analyzer to extend or skip a timing cycle, and may alsoeliminate a need for additional sample volume.

One possible way to conduct the spectrophotometric measurement after themetering tip is removed from the proboscis is to first seal or crimp theend of the metering tip, spontaneously forming a cuvette for holding theremaining portion of the sample during the measurement.

An improved analyzer process according to the principles of the presentinvention may include the steps of sample handling, aspirating a portionof the sample into a metering tip, and dispensing a portion of thesample onto a test element or slide. Next, a proboscis holding themetering tip may move to a tip ejection position. Then, a positionsensor may be used to detect that the proboscis and metering tip havemoved to the tip ejection position, and the sensor may trigger a clampto hold the tip in position while the proboscis lifts away. Preferablyafter a short delay to let the sample fluid settle, a spectrophotometerreading is taken through the cone of the tip. The clamp may then bereleased, allowing the tip to fall into a disposal container.

In optional steps, a metering pump may pull sample fluid a shortdistance up into the tip to form a small bubble of air at the tip's end,and the end of the metering tip may be sealed to form a virtual cuvette.

Another optional step of the present invention may involve aspirating aselected auxiliary volume of sample liquid from the tip or cuvette afterthe sample quality measurement, and passing this auxiliary sample to awet chemistry analyzer system. Or, rather than a wet chemistry system,the auxiliary sample may be passed to a diluter system, where it isdiluted and passed on to the sample processing apparatus for repeatingat least one clinical chemistry test and analysis on the diluted liquid.

Accordingly, some advantages of the present system and method includeimproved throughput, the capability to use much smaller sample liquidvolumes, eliminating any need for a separate supply of cuvettes inaddition to the metering tips. An additional advantage lies in providingfor detection through a cone of the metering tip, rather than throughany label that may be on a primary patient collection container.

Additional advantages of the present invention include conductingspectrophotometric analysis in a simpler and less expensive manner.Another advantage lies in obtaining results of spectrophotometricanalysis in less time, without extending or omitting a timing cycle.

These and various other objects, advantages and features of theinvention will become apparent from the following description andclaims, when considered in conjunction with the appended drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an external perspective view of an analyzer system, arrangedaccording to the principles of the present invention;

FIG. 2 is a perspective view of a portion of an analyzer system;

FIGS. 3–9 are partially diagrammatic views of portions of an analyzersystem, illustrating operation of the analyzer according to a method ofthe present invention;

FIGS. 10–13 are partially diagrammatic views of portions of an analyzersystem, showing in particular a cone portion of a metering tip duringoperation of the analyzer according to a method of the presentinvention;

FIG. 14 is a partial perspective view of a sample handling system and asample metering system of an analyzer; and

FIG. 15 is a partial perspective view of a clinical chemistry system ofan analyzer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description of the preferred embodiments of the presentinvention is merely illustrative in nature, and as such it does notlimit in any way the present invention, its application, or uses.Numerous modifications may be made by those skilled in the art withoutdeparting from the true spirit and scope of the invention.

Referring to the drawings, several components of a clinical analyzer aredepicted, with one of the preferred embodiments of the present inventionbeing shown generally at 10. The illustrated analyzer 10 is of courseonly one of many different analyzer designs within the scope of thepresent invention.

In the illustrated embodiment, the analyzer 10 illustrated in thedrawings includes a main operational unit 12 and an operator controlunit 14. The operational unit 12 preferably includes an outer housing16, a sample handling or supply system 18 for holding and organizing aseries of primary patient collection containers 20, a sample meteringsystem 22 for aspirating and dispensing portions of individual samples24 and moving them among the various operating stations of the analyzer10, and a sample processing system 26 for conducting the desiredclinical tests on and analysis of the samples 24. The operator controlunit 14 preferably includes a monitor and keyboard 28 for operating theanalyzer 10 as well as the computers of the analyzer 10, including forexample a master computer, scheduling computer, and subsystemscomputers.

The selection of a particular design for the sample handling system 18is not important for the present invention, but may include a holdingsurface or bay 30 for supporting a series of sample trays 32, eachholding several primary patient collection containers 20. The samplehandling system may be arranged along the lines of the sample handlingsystem 18 shown in FIG. 15, but may of course have a variety of designs.Such other designs may include a rectangular sample bay, linear sampletrays, or any other suitable design.

The “primary patient collection container” is a container in whichpatient biological liquid, usually blood, is initially placed. Thecontainer is generally provided a label and processed in preparation fortesting. In the case of whole blood, such processing often includesphase separation in which liquid serum or plasma is separated from thecellular phase comprising the blood cells, usually with a gel separationbarrier.

The sample metering system 22 may preferably be arranged along the linesof that shown in FIG. 2, but may also have a variety of designs. Thesample metering system 22 shown in FIG. 2 includes a base 34 mounted forselective longitudinal movement on a horizontal rail 36, a horizontaldrive mechanism (not shown), a vertical carriage 38 coupled to avertical drive mechanism 40 for selective vertical movement with respectto the base 34, and a proboscis 42 affixed to the vertical rack 38.Essentially, the proboscis 42 can move in at least two dimensions withina vertical plane defined by the rail 36. Such a metering control system22 is described in, for example, U.S. Pat. No. 4,340,390.

Because of the sensitive nature of the sample liquid 24, it is desirableto operate the sample metering system 22 without allowing any portion ofthe proboscis 42 to contact sample liquid 24. Accordingly, the analyzer10 preferably has a supply of the tubular metering tips 44 which arepreferably disposable. The metering tips 44 shown in the drawings can beremovably attached to an end of the proboscis 42, and have a tubularbody 46, and intermediate cone 48, and a capillary tip 50.

A metering pump 52 is operatively coupled to a lumen defined by theproboscis 42 and the metering tip 44, for selectively generating variousamounts of partial vacuum and partial pressure. The metering pump 52,and therefore the metering assembly 22, is capable of using such partialvacuum and partial pressure to selectively aspirate and dispense amountsof sample liquid 24.

As will be readily evident, the material of the metering tips 44 ispreferably selected to allow transmission of near-infrared and adjacentvisible radiation. The metering tips 44 are preferably free of labels,since any labeling can be done exclusively on the primary collectioncontainers 20. Materials useful for metering tips 44 may includepolymers such as polypropylene and polyethylene.

The sample processing system 26 has equipment for performing variousclinical chemistry tests, which may include a thin film system having asupply of reagents and test element slides, and/or wet chemistryapparatus, and any other suitable clinical chemistry testing system. Theillustrated sample processing system 26 has a supply of thin filmslides, rotating incubator 56, reference fluid supply 58, electrometer60, immuno-wash fluid system 62, and other clinical chemistry equipmentshown in the drawings. The sample processing system 26 may includeequipment to perform potentiometric, calorimetric or other clinicalchemistry tests.

The analyzer 10 preferably includes conventional clinical chemistry forvarious assays that use test elements. The term “test element” means anyreaction vessel in which at least one reagent has been pre-supplied, forexample thin film or dry slide test elements. Such slides are describedin, for example, U.S. Pat. No. 3,992,158. Another example of a testelement would include a cup or well having a cavity pre-coated with oneor more antibodies, as is described in U.S. Pat. No. 5,441,895.

In operation, the sample metering system 22 moves about the analyzer 10among the various operating stations in a cyclical, periodic manner.First, the sample metering system 22 moves from an initial or homeposition to a position above a tray of disposable metering tips 44,where the proboscis 42 descends into and picks up a metering tip 44 fromthe tip tray. The sample metering system 22 then moves the proboscis 42over the sample handling system 18. The proboscis 42 descends andinserts the metering tip 44 into a primary collection container 20. Themetering pump 52 creates a partial vacuum, and a portion of the patientsample 24 is aspirated into the tip 44.

Next, the sample metering system 22 moves over a test element, themetering pump 50 creates a partial pressure, and a portion of the sampleliquid 24 in the metering tip 44 is dispensed onto the test element.Thereafter, the test element may be transferred to an incubator 56 whereit incubates (possibly also with rotation of the incubator), until it isread or detected at a test station. The test station may generallyinclude a colorimetric or potentiometric detector.

Additional steps and processes may be performed by the sample processingsystem 26 in a conventional manner. When finished, the timing cyclerepeats. The time required to complete such a cycle defines theheartbeat of the analyzer.

One proposal that has been considered is to simply incorporate samplequality measurements into the timing cycle of the analyzer, in a serialmanner. However, such a serial approach would undesirably lengthen thetiming cycle, or require the analyzer to skip a timing cycle to conductthe sample quality measurement. This approach would thus cause anundesirable decrease in analyzer throughput, since the sample qualityreading would take as much time as metering a sample onto a new testelement.

This approach would also require substantial analyzer softwaremodifications, to enable the proboscis 42 and metering tip 44 to move toa new location where the sample integrity read block is positioned.Also, additional sample fluid would be required, because the level ofthe sample fluid must be in the cone of the metering tip for an accuratereading.

Accordingly, the sample quality system of the present invention providesthe novel concept of conducting the sample quality measurement in aparallel process to the conventional sample processing system. Theconcept is to have a sample quality device grab the tip as the meteringsystem is about to eject it. This parallel process enables the samplequality system to take several seconds to move the tip into position,make the sample quality reading, and dispose of the tip withoutimpacting the analyzer timing cycle or throughput.

One example of the novel sample quality system 62 of the presentinvention is shown in the drawings. In particular, operation of a samplequality system 62 is depicted in FIGS. 3–13. FIGS. 3–5 show theproboscis 42 before and after picking up a disposable metering tip 44,and then after some sample liquid 24 has been aspirated into the tip 44.

Another novel feature of the present invention is illustrated in FIGS.6–9, which occur after the sample processing system 26 has conducted thevarious operations and tests during a normal timing cycle, and beforethe tip 44 is removed from the proboscis 42 and eventually discarded.According to this novel feature, the sample quality system 62 will firstcrimp the end of the tip 44 to prevent sample fluid from being lostduring and after the tip ejection process. As a result, the crimped tipessentially becomes a virtual cuvette 64 for holding the sample fluid.

The sample quality system 62 can then perform an absorption measurementwhile the sample metering system 22 is picking up the next tip 44 andaspirating fluid 24, continuing the primary timing cycle.

These additional steps are illustrated in FIGS. 6–9. First, the sampleliquid 24 is further aspirated to a slightly higher level in themetering tip 44, leaving a portion of the capillary tip 50 empty offluid 24. Any suitable type of heated die or clamp 66 may be used toseal a portion of the capillary tip 50. Following removal of themetering tip 44 from the proboscis 42, the metering tip 44 is sealed andbecomes a cuvette 64 as shown in FIG. 8, and the sample qualitymeasurement is performed as shown in FIG. 9.

The sample quality measurement of the present invention is performed bya spectrophotometer 68. The spectrophotometer 68 is shown onlydiagrammatically in the drawings, and it is not described in any detail,because any suitable spectrophotometer may be used, provided it operatesacceptably and is preferably responsive to radiation in thenear-infrared and adjacent visible light regions with sufficientprecision. The tern “near-infrared and adjacent visible radiation” orlight means radiation between about 400 and 2500 nm, and preferablybetween about 475 and 1075 nm. Useful translucent or transparentmaterials for the metering tips that allow desired spectral penetrationare those commonly used to manufacture clinical analyzer disposabletips, including polypropylene and polyethylene.

In operation, the cuvette 64 is positioned at the sample qualitystation, and a beam of preferably near-infrared and adjacent visiblewavelengths is passed through the cuvette 64 and any liquid inside. Theradiation transmitted is spectrophotometrically analyzed by thespectrophotometer 68. The signal produced by the detector is thencorrelated with the concentration of target substances.

A preferred set of target substances are those that indicate samplequality, specifically those selected from the group consisting ofhemoglobin, lipids, bilirubin, and biliverdin. However, any targetsubstance capable of spectrophotometric detection by its absorptionspectra can be correlated and detected by this invention. Morespecifically, certain assays that have previously been conducted on theslide test element, can now be conducted through the tipspectrophotometrically.

In addition to testing for sample quality, any target substance that isanalyzable spectrophotometrically, preferably by using near-infrared andadjacent visible wavelengths, can be analyzed by the spectrophotometerwhile the patient sample is in the metering tip. Such possible targetsubstances include hemoglobin, albumin and glucose, among others. Bytesting these target substances in the tip, it is not necessary toconduct (and the analyzer preferably omits), further assays for themwhen the sample is tested by the sample processing system during thenormal timing cycle.

This technique enhances greatly the total throughput of the analyzer 10,because the spectrophotometric detection is performed in a parallelprocess from the standard analyzer process. Also, the spectrophotometricmeasurement through the tip 44 may require only about four seconds forall the target substances, compared to about four seconds for eachseparate assay performed on a slide test element. In addition, the “timeto result” is also improved by spectrophotbmetric analysis through thetip to approximately four seconds for analysis through the tip, comparedto approximately five minutes on a slide test element.

Testing in this manner while sample liquid is in the metering tip mayalso be done with some kind of temperature control. Such sample liquidtemperature control may be done by controlling the temperature at thetest station, but can also be done by heating or cooling the sampleliquid in the primary containers, or while the liquid is in the meteringtip, etc.

Although the tests conducted by the sample processing system 26preferably omits those spectrophotometric tests done through the tip 44,it is also possible to repeat such assays during the primary timingcycle, to obtain a check of their accuracy.

In addition, another optional step of the present invention may involveaspirating a selected auxiliary volume of sample liquid from the tip orcuvette after the sample quality measurement, and passing this auxiliarysample to a wet chemistry analyzer system. Moreover, rather than a wetchemistry system, the auxiliary sample may be passed to a dilutersystem, where it is diluted and passed on to the sample processingapparatus for repeating at least one clinical chemistry test andanalysis on the diluted liquid.

It should be understood that an unlimited number of configurations forthe present invention could be realized. The foregoing discussiondescribes merely exemplary embodiments illustrating the principles ofthe present invention, the scope of which is recited in the followingclaims. Those skilled in the art will readily recognize from thedescription, claims, and drawings that numerous changes andmodifications can be made without departing from the spirit and scope ofthe invention.

1. A clinical analyzer for analyzing at least a portion of a liquidsample, comprising: sample handling apparatus having one or more samplecontainers holding an amount of sample liquid; sample metering apparatushaving a proboscis defining a metering lumen, one or more tips with atubular shape and a metering aperture at one end, and a metering pumpcoupled with the proboscis lumen; the tips being removably attachable tothe proboscis and allowing fluid communication between the metering pumpand the metering aperture through the proboscis lumen; sample processingapparatus having one or more test elements, an incubator and at least athin film clinical chemistry system and a wet chemistry clinical testingsystem for conducting clinical tests on the liquid samples; and samplequality apparatus having a spectrophotometer and a tip end clampingdevice; the analyzer having several operating stations: (a) an initialaspiration position where a metering aperture of the tip can beperiodically immersed in sample liquid held within one of the samplecontainer; the metering pump adapted to create a partial vacuum to causea selected volume of sample liquid to be aspirated from a samplecontainer into the tip; (b) a dispensing position where the meteringpump can create a partial pressure to cause a portion of the sampleliquid to be dispensed from the tip onto a test element; (c) a thin filmclinical chemistry testing position; (d) a sample quality measurementposition; and (e) a wet chemistry testing position.